The introduction of potent direct acting antivirals (DAA) has significantly improved the treatment response of patients with chronic HCV infection. However, at present, these interferon (IFN)-free treatment regimens are not available for most patients worldwide, partly due to the high costs. The WHO estimates IFN&#945;-based therapy will remain the sole available therapy particularly middle and low-income countries for the next several years. In addition, IFN&#945; remains important for HCV genotype 3 infected patients as part of a combination therapy with DAAs. The response rate to IFN-based therapy is negatively influenced by the pre-activation state of the innate immune response, which has a genetic component. At present, it is not known whether the responsiveness to IFN&#945;-based therapy can be improved. We therefore asked whether a rapid reduction in viremia within the first 24 hours of therapy with DAAs improves the IFN response of patients who had failed a standard course of pegylated IFN (PegIFN)/ribavirin (RBV) therapy in the past. Thirty-one HCV-infected non-responders to previous PegIFN/RBV therapy were studied for NK cell responses during subsequent successful therapy, in which DAAs were either added to PegIFN/RBV or given alone. NK cell expression of pSTAT1 and the IFN-stimulated genes STAT1 and TRAIL were assessed as a read-out for IFN-responsiveness. The 24h-virological response to therapy with PegIFN/RBV/DAAs correlated with an increase in pSTAT1 and STAT1 expression in NK cells, which was greater than during the previous unsuccessful course of PegIFN/RBV therapy. This was associated with an increase in NK cell function as measured by increased TRAIL secretion and expression of the degranulation marker CD107a that serves as a readout for cytotoxicity. Collectively, these results show that IFN-responsiveness can be improved by inhibiting HCV replication. This may provide a rationale for a brief treatment with DAAs followed by PegIFN/RBV therapy to reduce the overall treatment costs in low and middle-income countries. Improved NK cell responsiveness to IFN may also be relevant for improved immune surveillance and prevention of viral relapse.